title: Sildenafil exposure and hemodynamic effect after stage II single-ventricle surgery.
abstract: OBJECTIVE
  To determine sildenafil exposure and hemodynamic effect in children after stage II single-ventricle surgery.
  
  
  METHODS
  Prospective, dose escalation trial.
  
  
  METHODS
  Single-center, pediatric catheterization laboratory.
  
  
  METHODS
  Twelve children poststage II single-ventricle surgical palliation and undergoing elective cardiac catheterization: median age 1.9 years (range, 0.8, 4.0), weight 11 kg (8, 13), nine females, and 10 with a single right ventricle.
  
  
  METHODS
  Catheterization and echocardiography performed before and immediately after single-dose IV sildenafil (0.125, 0.25, 0.35, or 0.45 mg/kg over 20 min).
  
  
  METHODS
  Peak sildenafil and desmethyl sildenafil concentration, change in hemodynamic parameters measured by cardiac catheterization and echocardiography including indexed pulmonary vascular resistance, and myocardial performance.
  
  
  RESULTS
  Maximum sildenafil concentrations ranged from 92 to 775 ng/mL and were above the in vitro threshold needed for 77% phosphodiesterase type 5 (PDE-5) inhibition in 80% of subjects and 90% inhibition in 80% of subjects with doses ≥0.35 mg/kg. Sildenafil lowered pulmonary vascular resistance index in all 12 subjects (median pulmonary vascular resistance index 2.2 [range, 1.6, 7.9]; decreased to 1.7 [1.2, 5.4] WU × m; p < 0.01) with no dose-response effect. Sildenafil improved pulmonary blood flow (+8% [0, 20], p = 0.04) and saturations (+2% [0, 16], p = 0.04) in those with baseline pulmonary vascular resistance index ≥ 2 WU × m (n = 7). Change in saturations correlated inversely with change in pulmonary vascular resistance index (r = 0.74, p < 0.01). Sildenafil also lowered mean blood pressure (-12% [-20, +10]; p = 0.04). There was no change in cardiac index and no effect on myocardial performance. There were no adverse events.
  
  
  CONCLUSIONS
  Sildenafil demonstrated nonlinear exposure with high interindividual variability but was well tolerated and effectively lowered pulmonary vascular resistance index in all subjects. Sildenafil did not acutely improve myocardial performance or increase cardiac index.
authors.affiliation: Department of Pediatrics, Duke University Medical Center, Durham, NC, USA. kevin.hill@duke.edu
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Hill
authors.forename: Robert D
authors.initials: RD
authors.lastname: Tunks
authors.forename: Piers C A
authors.initials: PC
authors.lastname: Barker
authors.forename: Daniel K
authors.initials: DK
authors.lastname: Benjamin
authors.forename: Michael
authors.initials: M
authors.lastname: Cohen-Wolkowiez
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Fleming
authors.forename: Matthew
authors.initials: M
authors.lastname: Laughon
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: Li
mesh_terms: D006328:Cardiac Catheterization; D017024:Chemotherapy, Adjuvant; D002648:Child; D002675:Child, Preschool; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006352:Heart Ventricles / Q000002:abnormalities* / Q000000981:diagnostic imaging / Q000601:surgery; D006439:Hemodynamics / Q000187:drug effects*; D006801:Humans; D018636:Hypoplastic Left Heart Syndrome / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000601:surgery; D007223:Infant; D007275:Injections, Intravenous; D016014:Linear Models; D008297:Male; D010166:Palliative Care / Q000379:methods; D058986:Phosphodiesterase 5 Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D010879:Piperazines / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D011446:Prospective Studies; D011687:Purines / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D016896:Treatment Outcome; D014463:Ultrasonography; D014655:Vascular Resistance / Q000187:drug effects
chemical_list: D058986:Phosphodiesterase 5 Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D000068677:Sildenafil Citrate